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Dowell CK, Lau JYN, Antinucci P, Bianco IH
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Kinematically distinct saccades are used in a context-dependent manner by lar...

CURRENT BIOLOGY 2024 OCT 7; 34(19):?
Saccades are rapid eye movements that are used by all species with good vision. In this study, we set out to characterize the complete repertoire of larval zebrafish horizontal saccades to gain insight into their contributions to visually guided behavior and underlying neural control. We identified five saccade types, defined by systematic differences in kinematics and binocular coordination, which were differentially expressed across a variety of behavioral contexts. Conjugate saccades formed a large group that serves at least four functions. These include fast phases of the optokinetic nystagmus, visual scanning in stationary animals, and shifting gaze in coordination with body turns. In addition, we discovered a previously undescribed pattern of eye-body coordination in which small conjugate saccades partially oppose head rotation to maintain gaze during forward locomotion. Convergent saccades were coordinated with body movements to foveate prey targets during hunting. Detailed kinematic analysis showed that conjugate and convergent saccades differed in the millisecond coordination of the eyes and body and followed distinct velocity main sequence relationships. This challenges the prevailing view that all horizontal saccades are controlled by a common brainstem circuit and instead indicates saccade-type-specific neural control.
Villasante CM, Deng XY, Cohen JE, Hudspeth AJ
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Nanomechanics of wild- type and mutant dimers of the inner- ear tip- link pro...

PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA 2024 OCT 1; 121(40):? Article e2404829121
Mechanical force controls the opening and closing of mechanosensitive ion channels atop the hair bundles of the inner ear. The filamentous tip link connecting transduction channels to the tallest neighboring stereocilium modulates the force transmitted to the channels and thus changes their probability of opening. Each tip link comprises four molecules: a dimer of protocadherin 15 (PCDH15) and a dimer of cadherin 23, all of which are stabilized by Ca2+ binding. Using a high- speed optical trap to examine dimeric PCDH15, we find that the protein's mechanical properties are sensitive to Ca2+ and that can therefore modulate its stiffness without undergoing large unfolding events under physiological conditions. The experimentally determined stiffness of PCDH15 accords with published values for the stiffness of the gating spring, the mechanical element that controls the opening of mechanotransduction channels. When PCDH15 exhibits a occur more frequently under tension and refolding events occur less often than for the the gating spring is critical to the appropriate transmission of force to transduction channels, and hence to hearing.
Brousset P, Abel L, Froguel P, Quintana-Murci L, Solassol J, Ardaillou R, Del...
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Contribution of next generation DNA sequencing techniques in practice and med...

BULLETIN DE L ACADEMIE NATIONALE DE MEDECINE 2024 OCT; 208(8):1141-1149
For more than ten years, France has implemented several initiatives and programs aimed at promoting and exploiting the potential of next-generation sequencing (NGS) techniques in various fields. The country has a number of highly equipped next-generation sequencing platforms and research centers specializing in NGS. These infrastructures provide sequencing services to academic researchers, medical institutions and industrial partners. NGS is widely used in medical biology, particularly in molecular medicine and genetics, to develop personalized medicine approaches and in genomics research. Through several hearings with experts in the field of medical genetics and paleo-genomics, we obtained an overview of the contribution of NGS techniques to medicine and population genetics. We envisage several perspectives for the use of NGS in parallel with the biotechnological and bioinformatics progresses dedicated to it. (c) 2024 Published by Elsevier Masson SAS on behalf of l'Academie nationale de medecine.
Unda SR, Pomeranz LE, Marongiu R, Yu XF, Kelly L, Hassanzadeh G, Molina H, Va...
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Bidirectional regulation of motor circuits using magnetogenetic gene therapy

SCIENCE ADVANCES 2024 OCT 9; 10(41):? Article eadp9150
Here, we report a magnetogenetic system, based on a single anti-ferritin nanobody-TRPV1 receptor fusion protein, which regulated neuronal activity when exposed to magnetic fields. Adeno-associated virus (AAV)-mediated delivery of a floxed nanobody-TRPV1 into the striatum of adenosine-2a receptor-Cre drivers resulted in motor freezing when placed in a magnetic resonance imaging machine or adjacent to a transcranial magnetic stimulation device. Functional imaging and fiber photometry confirmed activation in response to magnetic fields. Expression of the same construct in the striatum of wild-type mice along with a second injection of an AAVretro expressing Cre into the globus pallidus led to similar circuit specificity and motor responses. Last, a mutation was generated to gate chloride and inhibit neuronal activity. Expression of this variant in the subthalamic nucleus in PitX2-Cre parkinsonian mice resulted in reduced c-fos expression and motor rotational behavior. These data demonstrate that magnetogenetic constructs can bidirectionally regulate activity of specific neuronal circuits noninvasively in vivo using clinically available devices.
Braunscheidel KM, Voren G, Fowler CD, Lu Q, Kuryatov A, Cameron MD, Ibañez-Ta...
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SR9883 is a novel small-molecule enhancer of α4β2*nicotinic acetylcholine rec...

FRONTIERS IN MOLECULAR NEUROSCIENCE 2024 SEP 5; 17(?):? Article 1459098
Background Most smokers attempting to quit will quickly relapse to tobacco use even when treated with the most efficacious smoking cessation agents currently available. This highlights the need to develop effective new smoking cessation medications. Evidence suggests that positive allosteric modulators (PAM) and other enhancers of nicotinic acetylcholine receptor (nAChR) signaling could have therapeutic utility as smoking cessation agents.Methods 3-[3-(3-pyridyl)-1,2,4-oxadiazol-5-yl]benzonitrile (NS9283) was used as a starting point for medical chemistry efforts to develop novel small molecule enhancers of alpha 4 beta 2* nAChR stoichiometries containing a low-affinity agonist binding site at the interface of alpha 4/alpha 4 and alpha 4/alpha 5 subunits.Results The NS9283 derivative SR9883 enhanced the effect of nicotine on alpha 4 beta 2* nAChR stoichiometries containing low-affinity agonist binding sites, with EC50 values from 0.2-0.4 mu M. SR9883 had no effect on alpha 3 beta 2* or alpha 3 beta 4* nAChRs. SR9883 was bioavailable after intravenous (1 mg kg-1) and oral (10-20 mg kg-1) administration and penetrated into the brain. When administered alone, SR9883 (5-10 mg kg-1) had no effect on locomotor activity or intracranial self-stimulation (ICSS) thresholds in mice. When co-administered with nicotine, SR9883 enhanced locomotor suppression and elevations of ICSS thresholds induced by nicotine. SR9883 (5 and 10 mg kg-1) decreased responding for intravenous nicotine infusions (0.03 mg kg-1 per infusion) but had no effect on responding for food rewards in rats.Conclusions These data suggest that SR9883 is useful for investigating behavioral processes regulated by certain alpha 4 beta 2* nAChR stoichiometries. SR9883 and related compounds with favorable drug-like physiochemical and pharmacological properties hold promise as novel treatments of tobacco use disorder.
Le Pen J, Paniccia G, Kinast V, Moncada-Velez M, Ashbrook AW, Bauer M, Hoffma...
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A genome-wide arrayed CRISPR screen identifies PLSCR1 as an intrinsic barrier...

PLOS BIOLOGY 2024 SEP; 22(9):? Article e3002767
Interferons (IFNs) play a crucial role in the regulation and evolution of host-virus interactions. Here, we conducted a genome-wide arrayed CRISPR knockout screen in the presence and absence of IFN to identify human genes that influence Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) infection. We then performed an integrated analysis of genes interacting with SARS-CoV-2, drawing from a selection of 67 large-scale studies, including our own. We identified 28 genes of high relevance in both human genetic studies of Coronavirus Disease 2019 (COVID-19) patients and functional genetic screens in cell culture, with many related to the IFN pathway. Among these was the IFN-stimulated gene PLSCR1. PLSCR1 did not require IFN induction to restrict SARS-CoV-2 and did not contribute to IFN signaling. Instead, PLSCR1 specifically restricted spike-mediated SARS-CoV-2 entry. The PLSCR1-mediated restriction was alleviated by TMPRSS2 overexpression, suggesting that PLSCR1 primarily restricts the endocytic entry route. In addition, recent SARS-CoV-2 variants have adapted to circumvent the PLSCR1 barrier via currently undetermined mechanisms. Finally, we investigate the functional effects of PLSCR1 variants present in humans and discuss an association between PLSCR1 and severe COVID-19 reported recently. Interferons (IFNs) have a role in the regulation of virus-host interactions. This study uses genome-wide CRISPR knockout screen data to identify 28 genes that impact SARS-CoV-2 infection, including PLSCR1, which restricts spike-mediated SARS-CoV-2 entry independently of its IFN-related role.
El Kettani A, Ouair H, Marnissi F, El Bakkouri J, Chevalier R, Lorenzo L, Kho...
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Case Report of Two Independent Moroccan Families with Syndromic Epidermodyspl...

VIRUSES-BASEL 2024 SEP; 16(9):? Article 1415
Epidermodysplasia verruciformis (EV) is a rare genodermatosis caused by beta-human papillomaviruses (HPV) in immunodeficient patients. EV is characterized by flat warts and pityriasis-like lesions and might be isolated or syndromic, associated with some other infectious manifestations. We report here three patients from two independent families, with syndromic EV for both of them. By whole exome sequencing, we found that the patients carry new homozygous variants in STK4, both leading to a premature stop codon. STK4 deficiency causes a combined immunodeficiency characterized by a broad infectious susceptibility to bacteria, viruses, and fungi. Auto-immune manifestations were also reported. Deep immunophenotyping revealed multiple cytopenia in the three affected patients, in particular deep CD4(+) T cells deficiency. We report here the fourth and the fifth cases of the syndromic EV due to STK4 deficiency.
Short B
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Grammotoxin increases its toxic behavior

JOURNAL OF GENERAL PHYSIOLOGY 2024 SEP 25; 156(10):? Article e202413665
This JGP study reveals that in addition to voltage-gated Ca2+ and K+ channels, omega-grammotoxin-SIA also inhibits voltage-gated Na+ channel currents.
Hayrapetyan A, Tumasyan A, Adam W, Andrejkovic JW, Arnold B, Bergauer H, Berg...
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Performance of the CMS electromagnetic calorimeter in pp collisions at √s<...

JOURNAL OF INSTRUMENTATION 2024 SEP; 19(9):? Article P09004
The operation and performance of the Compact Muon Solenoid (CMS) electromagnetic calorimeter (ECAL) are presented, based on data collected in pp collisions at root s = 13 TeV at the CERN LHC, in the years from 2015 to 2018 (LHC Run 2), corresponding to an integrated luminosity of 151 fb(-1). The CMS ECAL is a scintillating lead-tungstate crystal calorimeter, with a silicon strip preshower detector in the forward region that provides precise measurements of the energy and the time-of-arrival of electrons and photons. The successful operation of the ECAL is crucial for a broad range of physics goals, ranging from observing the Higgs boson and measuring its properties, to other standard model measurements and searches for new phenomena. Precise calibration, alignment, and monitoring of the ECAL response are important ingredients to achieve these goals. To face the challenges posed by the higher luminosity, which characterized the operation of the LHC in Run 2, the procedures established during the 2011-2012 run of the LHC have been revisited and new methods have been developed for the energy measurement and for the ECAL calibration. The energy resolution of the calorimeter, for electrons from Z boson decays reaching the ECAL without significant loss of energy by bremsstrahlung, was better than 1.8%, 3.0%, and 4.5% in the vertical bar eta vertical bar intervals [ 0.0, 0.8], [0.8, 1.5], [1.5, 2.5], respectively. This resulting performance is similar to that achieved during Run 1 in 2011-2012, in spite of the more severe running conditions.
Karaaslan BG, Rosain J, Bustamante J, Kiykim A
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Interferon Gamma in Sickness Predisposing to Mycobacterial Infectious ...

BALKAN MEDICAL JOURNAL 2024 SEP; 41(5):326-332
In recent decades, the prevalence of inborn errors of immunity has increased, necessitating the development of more effective treatment and care options for these highly morbid conditions. Due to these "experiments of nature," the complicated nature of the immune system is being revealed. Based on the functional and molecular tests, targeted therapies are now being developed which offer a more effective approach and reduce damage. This study aimed to investigate a key cytokine of the cellular immune response, interferon-gamma (IFN-gamma), gamma ), which is linked to Mendelian susceptibility to Mycobacterial disease, and its potential as a therapeutic option for IFN-gamma gamma deficiency.